Multiple sclerosis (MS), also known as disseminated sclerosis or encephalomyelitis disseminata, is a chronic, often disabling disease in which the insulating covers of nerve cells in the central nervous system (CNS) are damaged. Noseworthy et al., N. Engl. J. Med. 2000, 343, 938-952; Ebers, Lancet Neurol. 2008, 7, 268-277; Luessi et al., Expert. Rev. Neurother. 2012, 12, 1061-1076. This damage disrupts the ability of parts of the nervous system to communicate, resulting in a wide range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Compston et al., Lancet 2008, 372, 1502-1517. The most common clinical signs and symptoms of MS include sensory disturbance of the limbs (˜30%), partial or complete visual loss (˜15%), acute and subacute motor dysfunction of the limbs (˜13%), diplopia (7%), and gait dysfunction (5%). Unfortunately, fifty percent of MS patients will need help to walk within 15 years after the onset of the disease. Noseworthy et al., N. Engl. J. Med. 2000, 343, 938-952.
The underlying mechanism of MS is thought to be either destruction by the immune system or failure of the myelin-producing cells. Nakahara et al., Clin. Rev. Allergy Immunol. 2012, 42, 26-34. Thus, MS is also considered as an immune-mediated disease. MS is thought to be triggered in genetically susceptible individuals by environmental factors such as infections. Ascherio et al., Ann. Neurol. 2007, 61, 288-299; Ascherio et al., Ann. Neurol. 2007, 61, 504-513; Compston et al., Lancet 2008, 372, 1502-1517.
The worldwide prevalence of MS is estimated at between 1.1 and 2.5 million cases of MS. Pugliatti et al., Clin Neurol. Neurosurg. 2002, 104, 182-191. Like many other immune-mediated diseases, MS is also more prevalent in women, especially those of childbearing age, than in men. Orton et al., Lancet Neurol. 2006, 5, 932-936; Alonso et al., Neurology, 2008, 71, 129-135; Debouverie, J. Neurol. Sci. 2009, 286, 14-17; Ramagopalan et al., Neurology 2009, 73, 602-605.
Four main clinical phenotypes of MS are recognized: relapsing-remitting MS (RR-MS); primary progressive MS (PP-MS); progressive relapsing MS (PR-MS); and secondary progressive MS (SP-MS). Minagar, Scientifica 2013, Article ID 249101, 1-11. RR-MS is the most prevalent form of the disease and also the type with the greatest gender imbalance, characterized by clearly defined attacks of worsening neurologic function, followed by partial or complete recovery periods (remissions). Id.
Current treatment strategies include modifying the disease course, treating exacerbations (also called attacks, relapses, or flare-ups), managing symptoms, improving function and safety, and providing emotional support. As of today, MS remains an incurable disease and thus, MS patients often require lifelong treatment. Gawronski et al., Pharmacotherapy 2010, 30, 916-927; Krieger, Mt. Sinai J. Med. 2011, 78, 192-206; Minagar, Scientifica 2013, Article ID 249101, 1-11. Therefore, there is a clear and unmet need to develop effective therapeutics for treating a proliferative, inflammatory, neurodegenerative, or immune-mediated disease, e.g., MS.